1-45507455-C-T

Variant names:

• chr1-45507455-C-T
• rs200483477
• NM_015506.3:c.181C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM5 PP2 BP4_Moderate

The NM_015506.3(MMACHC):​c.181C>T​(p.Arg61Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000963 in 1,614,134 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R61P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00099 (1 hom.)
• Consequence: MMACHC NM_015506.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:1 O:1
• Conservation: PhyloP100: 1.24
• Publications: 4 publications found

Genes affected

MMACHC (HGNC:24525): (metabolism of cobalamin associated C) The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]

MMACHC Gene-Disease associations (from GenCC):

• methylmalonic aciduria and homocystinuria type cblC

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health, ClinGen, G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 42 pathogenic changes around while only 16 benign (72%) in NM_015506.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45507456-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 854802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 28 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: -1.0759 (below the threshold of 3.09). Trascript score misZ: -0.13772 (below the threshold of 3.09). GenCC associations: The gene is linked to methylmalonic aciduria and homocystinuria type cblC.
• BP4: Computational evidence support a benign effect (MetaRNN=0.077775985).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015506.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMACHC	NM_015506.3	MANE Select	c.181C>T	p.Arg61Trp	missense	Exon 2 of 4	NP_056321.2
	MMACHC	NM_001330540.2		c.10C>T	p.Arg4Trp	missense	Exon 2 of 4	NP_001317469.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMACHC	ENST00000401061.9	TSL:2 MANE Select	c.181C>T	p.Arg61Trp	missense	Exon 2 of 4	ENSP00000383840.4
	MMACHC	ENST00000616135.1	TSL:2	c.10C>T	p.Arg4Trp	missense	Exon 2 of 5	ENSP00000478859.1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152142 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000589 AC: 147 AN: 249498 AF XY: 0.000657

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000987 AC: 1443 AN: 1461874 Hom.: 1 Cov.: 32 AF XY: 0.00101 AC XY: 734 AN XY: 727236

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000881 AC: 76 AN: 86254

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00116 AC: 1295 AN: 1112004

Other (OTH) AF: 0.000894 AC: 54 AN: 60394

GnomAD4 genome AF: 0.000736 AC: 112 AN: 152260 Hom.: 1 Cov.: 31 AF XY: 0.000752 AC XY: 56 AN XY: 74456

African (AFR) AF: 0.000289 AC: 12 AN: 41552

American (AMR) AF: 0.000589 AC: 9 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00115 AC: 78 AN: 68004

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000853 Hom.: 1

Bravo AF: 0.000627

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000241 AC: 1

ESP6500EA AF: 0.00107 AC: 9

ExAC AF: 0.000677 AC: 82

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cobalamin C disease Uncertain:5 Benign:1 Other:1

Aug 20, 2021

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 61 of the MMACHC protein (p.Arg61Trp). This variant is present in population databases (rs200483477, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with cobalamin C deficiency (PMID: 16311595, 19370762). ClinVar contains an entry for this variant (Variation ID: 203824). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MMACHC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Uncertain significance and reported on 12/09/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Jul 14, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 14, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Apr 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:3

Jul 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as homozygous in a patient with cobalamin C deficiency who was also homozygous for R111X (PMID: 16311595); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28337550, 19370762, 16311595, 32439973)

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 09, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Uncertain:1

Apr 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.181C>T (p.R61W) alteration is located in exon 2 (coding exon 2) of the MMACHC gene. This alteration results from a C to T substitution at nucleotide position 181, causing the arginine (R) at amino acid position 61 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Disorders of Intracellular Cobalamin Metabolism Uncertain:1

May 22, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

MMACHC-related disorder Uncertain:1

Mar 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MMACHC c.181C>T variant is predicted to result in the amino acid substitution p.Arg61Trp. This variant has been reported in multiple individuals with methylmalonic aciduria and homocystinuria (Table 1, Lerner-Ellis et al. 2009. PubMed ID: 19370762). However, this variant has also been observed in cis with another loss-of-function MMACHC variant (p.Arg111*) in multiple individuals (Lerner-Ellis et al. 2005. PubMed ID: 16311595; Internal Data, PreventionGenetics). This variant is reported in 0.11% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Methylmalonic aciduria, type cblc Uncertain:1

Nov 01, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Methylmalonic acidemia with homocystinuria cblC Uncertain:1

Aug 02, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.078	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.2
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.38
MVP		0.95
MPC		0.037
ClinPred		0.059	T
GERP RS		4.4
Varity_R		0.32
gMVP		0.59
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200483477; hg19: chr1-45973127; COSMIC: COSV53114115; COSMIC: COSV53114115;